N-hydroxyalkyl-substituted 1,2,3,6-tetrahydro-pyridine and piperidine derivatives

ABSTRACT

The invention relates to novel N-hydroxy-substituted 1,2,3,6-tetrahydropyridine and piperidine derivatives of the formula ##STR1## wherein A, B, D, E, G, I and R are as defined in the specification, m is 0, 1 or 2, with the proviso that: 
     m is 0 or 2, or both G and I are hydrogen, when A is benzyl or halogen-monosubstituted benzyl group; and 
     m is 1, when A is 2-picolyl, as well as their pharmaceutically acceptable acid addition salts. The compounds of formula (I) are useful for enhancing the tolerance of mammals (including man) against hypoxic and/or ischaemic states as well as for treating the degenerative and functional disturbances arising from hypoxic and/or ischaemic results.

FIELD OF THE INVENTION

The invention relates to novel N-hydroxyalkyl substituted1,2,3,6-tetrahydropyridine and piperidine derivatives, to processes andintermediates for their preparation, to pharmaceutical compostionscontaining them and to their medical use.

BACKGROUND OF THE INVENTION

International Patent Application PCT/HU90/00076 describestetrahydropyridine derivatives structurally related to the compounds ofthe invention which are said to have antiamnesic activity. In contrastto the present compounds, however, said compounds can be considered asβ- or τ-amino ketone compounds the nitrogen atom of which is closed as aring member into said substituted tetrahydropyridine ring.

The invention relates to novel, therapeutically activeN-hydroxyalkyl-substituted 1,2,3,6-tetrahydropyridine and piperidinederivatives of the formula ##STR2## wherein A is hydrogen or halogen;alkoxy; cyano; phenyl; phenyl monosubstituted by halogen; benzyl; benzylmonosubstituted by halogen; 2-phenylethyl monosubstituted by halogen onthe phenyl moiety; or 2-picolyl group;

B is hydrogen; alkoxy or nitro;

D is hydrogen, halogen; or alkoxy; or

B and D together are a --CH═CH--CH═CH-- group;

R is hydrogen; alkyl or phenyl;

G is hydrogen;

I is hydrogen or hydroxy; or

G and I together are a single chemical bond;

E is for hydrogen, halogen, alkoxy or trifluoromethyl; and

m is 0, 1 or 2,

with the proviso that:

m is 0 or 2, or both G and I are hydrogen, when A is benzyl orhalogen-monosubstituted benzyl; and

m is 1, when A is 2-picolyl,

as well as their acid addition salts.

Alkyl group as used herein either in itself or as a moiety of anothergroup, is a straight or branched chain saturated hydrocarbon groupcontaining 1-10 carbon atoms such as methyl, ethyl, n- and isopropyl,n-, o-, sec- and tert-butyl groups as well as the various pentyl, hexyl,heptyl, octyl, nonyl and decyl groups. C₁₋₆ alkyl groups are preferred,C₁₋₄ alkyl groups are more preferable and methyl group is particularlyfavorable.

Halogen may mean fluorine, chlorine, bromine or iodine.

The following compounds are particularly preferred:

1-[4-(4-chlorobenzyl)phenyl]-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanol,

1-[4-(4-chlorobenzyl)phenyl]-3-(4-phenyl-1-piperidyl)propanol,

1-[4-(4-chlorobenzyl)phenyl]-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butanol,

3-[4-(4-fluorophenyl)-1-piperidyl]-1-(1,1'-biphenyl-4-yl)propanol,

3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dichlorophenyl)propanol.

The present invention also relates to a pharmaceutical composition fortreating conditions selected from hypoxia and ischaemia comprising anamount of a compound of formula (I) or a pharmaceutically acceptableacid addition salt thereof effective in treating such conditions and apharmaceutically acceptable carrier.

Furthermore, the present invention also relates to a process andintermediates for the preparation of the compounds of formula (I), aswell as acid addition salt thereof.

Additionally, the present invention relates to a process for thepreparation of pharmaceutical compositions comprising a compound offormula (I) or a pharmaceutically acceptable acid addition salt thereof.

The present invention also relates to a method of treatment, whichcomprises administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically accaptable acid addition saltthereof to a mammal (including man) for strengthening its toleranceagainst hypoxic and/or ischaemic conditions as well as for treatingdegenerative and functional disturbances arising from hypoxic and/orischaemic insults.

Surprisingly, it has been found that the compounds of formula (I) arecapable to protect the brain from the cognitive function-injuring effectof various harmful conditions, e.g. hypoxia and/or ischaemia; or theyare useful to enhance the tolerance against hypoxic and/or ischaemicconditions, respectively as well as to treat degenerative and functionaldisturbances arising from hypoxic and ischaemic insults.

The biological effects of compounds according to the invention arehereinafter illustrated by using the following test methods.

Male CFLP mice (from the Hungarian stock LATI) weighing 24-26 g each andspontaneously hypertensive (SH) male rats weighing 160-180 g each,respectively were used in these investigations. The compounds to betested were orally administered in a volume of 10 ml/kg one hour priorto starting the experiment.

ANTIHYPOXIC EFFECT IN MICE 1. The Cytotoxic Hypoxia Test

After a 1-hour pretreatment, the animals were intravenously injectedwith 5 mg/kg of potassium cyanide. Survival time was measured as aninterval lasting from the administration of potassium cyanide to thelast respiratory movement. In the groups consisting of 10 animals eachtreated with the compounds, the animals having a survival time longer by30% than the average survival time of the placebo-treated group wereconsidered to be protected. The ED₅₀ values (i.e. the doses beingeffective in 50% of the animals) were calculated from the percentage ofthe surviving animals by using probit analysis.

2. The Hypobaric Hypoxia Test

After a 16-hour starving and 1-hour pretreatment period, the animalswere placed in a desiccator of 6 liters volume, where the pressure wasdecreased to 170 mmHg within 20 seconds. The survival time wasregistered from this time point up to the last respiratory movement ofthe animals. Animals having a survival time longer by 30% than theaverage survival time of the control group were considered to beprotected. The ED₅₀ values were calculated from the percentage of theanimals protected by using probit analysis.

The results obtained are summarized in Table 1.

                  TABLE 1                                                         ______________________________________                                                 Oral ED.sub.50 (mg/kg)                                               Compound   Cytotoxic hypoxia                                                                          Hypobaric hypoxia                                     (Sign)     in mice      in SH rats                                            ______________________________________                                        A          11.9         18.5                                                  B          19.8         11.5                                                  C          18.8         7.3                                                   D          50.0         3.7                                                   E          >50.0        8.3                                                   Vincamine  27.0         27.9                                                  Piracetam  131.5        293.0                                                 ______________________________________                                         The chemical names of compound listed in Table 1 are as follows.              "A":                                                                          1[4(4-chlorobenzyl)phenyl2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanol     "B": 1[4(4-chlorobenzyl)phenyl3-(4-phenyl-1-piperidiyl)propanol;              "C":                                                                          1[4(4-chlorobenzyl)phenyl4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridiyl)butano     "D": 3[4(4-fluorophenyl)-1-piperidiyl1-(1,1biphenyl-4-yl)propanol; and        "E":                                                                          3[4(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl1-(2,4-dichlorophenyl)pro    anol.                                                                     

Various forms of hypoxia were used for investigating the compounds. Thefunctional disorganization and destruction of cells and death,respectively in otherwise healthy mice are caused by a decrease in theoxygen-saturation of haemoglobin in the hypobaric hypoxia and theinhibition of the mitochondrial respiratory enzyme in the cytotoxichypoxia. Spontaneously hypertensive (SH) rats are more sensitive againsthypoxic conditions than normotensive animals; similarly, patientssuffering from hypertension have a less chance of survival after hypoxicinjuries.

Vincamine [chemically(+)-14β-hydroxy-14α-methoxycarbonyl-14,15-dihydroeburnamenine] andpiracetam (chemically 2-oxo-1-pyrrolidinylacetic acid amide) were usedas reference drugs. Vincamine increases the oxygen supply (vasodilatoryeffect) and modulates the metabolic processes of brain(cerebroprotective effect) whereas piracetam improves mainly theadaptation ability of the brain in pathologic states.

The antihypoxic effect of vincamine is most pronounced in cytotoxichypoxia and in addition, it has a prominent tolerance-enhancing actionin hypobaric hypoxia. Essentially, piracetam exerts its effect in thesame two tests.

The compounds according to the invention are more active in both testsin comparison to the reference drugs. It is particularly favorable thatthe antihypoxic effect is strongest in spontaneously hypertensiveanimals, which is a substantial therapeutical advantage under pathologicconditions.

The antihypoxic effect of compound "A" is the most favorable, since itseffects are the same in the various tests of hypoxia and it is 2- or3-times as effective as vincamine.

ACUTE TOXICITY STUDY IN MICE

OF-1 mice of either sex weighing 19-21 g were used. The test compoundwas administered through a catheter inserted into the stomach. A seriesof solutions was prepared, the concentrations were chosen to give aconstant dosage volume of 0.1 ml/10 g. The observation time after thetreatment was 72 hours. The LD₅₀ value was calculated according toLitchfield and Wilcoxon from six dose responses (maximal dose 1000 mg/kgp.o., n=10).

    ______________________________________                                        Compound     LD.sub.50 (mg/kg p.o.)                                           ______________________________________                                        A            >1000                                                            E            >1000                                                            B              697                                                            ______________________________________                                    

The active agents of formula (I) can be formulated in pharmaceuticalcompositions by mixing them with non-toxic, inert, solid or liquidcarriers and/or auxiliaries commonly used in the therapy for parenteralor enteral administration. Useful carriers are e.g. water, gelatine,lactose, starch, pectin, magnesium stearate, talc, vegetable oils suchas peanut oil, olive oil and the like. The active agent can beformulated in any usual pharmaceutical composition, particularly solidcomposition, e.g. rounded or edged tablet, dragee or capsule such asgelatine capsule, pill, suppository and the like. The amount of thesolid active ingredient may be varied within a broad range in a dosageunit of the composition (tablet, capsule, one unit of the formulatedsolution and the like), preferably it is between about 25 mg and 1 g.Optionally, these compositions may also contain other commonly usedpharmaceutical auxiliaries, e.g. stabilizers, preservatives, wettingagents, emulsifying agents and the like. The compositions can beprepared in a known manner, e.g. by sieving, mixing, granulating andcompressing the components in the case of solid compositions. Thecompositions may be subjected to other usual operations of thepharmaceutical technology, e.g. sterilization.

The dose to be used may be varied between wide limits depending on thebody-weight and responsiveness of the person or animal to be treated, aswell as on the severity of the state to be influenced, frequency androute of administration; however, the suitable dose can easily bedetermined by a physician skilled in the art.

The proposed daily doses of the active compounds of the invention fororal or enteral administration to the subject for the treatment of theconditions referred to above are between 0.1 to 50 mg of the activeingredient per kg body weight; however, this limit may be exceededdepending on the severity of the pathological state to be treated sincethe toxicity of the compounds of the invention is low. The daily dose ofthe active compound may be administered once or in subdoses to thepatient to be treated.

According to an other aspect of the invention, there is provided aprocess for the preparation of compounds of the formula (I), whichcomprises treating an oxo derivative of the formula ##STR3## or an acidaddition salt thereof with a reducing agent in an organic solvent andthen, if desired, converting the obtained N-hydroxyalkyl-substituted1,2,3,6-tetrahydropyridine or piperidine derivative of formula (I),wherein A, B, D, R, G, I, E and m are as defined above, to an acidaddition salt thereof by reacting it with a mineral or organic acid.

Useful reducing agents for this purpose are complex metal hydrides,preferably sodium borohydride, though this reduction can also beaccomplished e.g. by means of the Meerwein-Ponndorf-Verley reduction[Ann. Chem. 444, 221 (1926); Angew. Chem. 39 138 (1926)], e.g. by usingan aluminium alkoxide in isopropanol medium.

The reduction of the oxo derivatives of formula (II) by sodiumborohydride is preferably carried out in such a way that an acidaddition salt of a compound of formula (II) is used as startingsubstance and the base is liberated in situ in the reaction medium. Thereduction is accomplished in a lower alcohol or in the mixture of suchan alcohol and water. In order to make the reaction complete, thereducing agent is employed in an excess or the temperature of thereaction is elevated to the boiling point in the final period.

The product obtained is isolated by filtration or extraction. It issuitable to dilute the reaction medium with water for completing theprecipitation of the product. When extraction is used, a part of thealcohol is evaporated, then the reaction mixture is diluted with waterand the product is extracted into a water-immiscible hydrocarbon,chlorinated hydrocarbon, ethyl acetate or ether. The final product maybe purified by recrystallization. If desired, the compounds of formula(I) obtained in the base form can be converted to their acid additionsalts by reacting them with an organic or inorganic acid for the saltformation in a known way. Hydrochloride salts are preferred.

The oxo compounds of formula (II) and their addition salts are alsonovel. These compounds can advantageously be prepared from hydrogenatedpyridine derivatives of the formula ##STR4## as starting material byeither of two methods, which comprises a) alkylating a compound offormula (III) with a halogenated ketone of formula ##STR5## wherein X ishalogen, preferably chlorine or bromine, to obtain compounds of formula(II), wherein m is 0 or 2; or

b) reacting a compound of formula (III) with an acetophenone orpropiophenone of formula ##STR6## wherein R¹ is hydrogen or methyl, inthe presence of formaldehyde under conditions of the Mannich's reaction[Arch. Pharm. 250, 647 (1912)] to obtain compounds of formula (II),wherein m is 1.

A number of substances of formula (IV), e.g. phenacyl halides,α-bromopropiophenone [J. Chem. Soc. 125, 2343 (1924)], desyl bromide or2-bromoacetophenone [Ann. 155, 68 (1870)] are known from the literature.Both latter compounds can be prepared by brominating the appropriateketone; whereas the compounds of formula (IV), wherein m is 2 are mainlyprepared by reacting an aromatic compound of formula ##STR7## wherein Bas well as D preferably are hydrogen, with 4-chlorobutyryl chlorideunder Friedel-Crafts condition.

Starting compounds of formula (V) are commercially available products.

Compounds of formula (VI) can be produced by reacting a compound offormula (V) with an appropiate acid chloride under Friedel-Craftsconditions. The ketone synthesis is not necessarily the final step ofpreparing the compounds of formula (VI); the formation of a substituenton the aromatic ring may also be the last step.

The invention is illustrated in detail by the following non-limitingExamples.

EXAMPLE 1 Preparation of1-(4-Chlorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanol

To a solution containing 1.2 g (0.03 mol) of sodium hydroxide in 50 mlof an 50% by volume ethanol/water mixture, 12.41 g (0.03 mol) of1-(4-chlorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanonehydrochloride and then, over 1 hour 1.17 g of sodium borohydride areadded. The suspension is heated at a temperature of 50° C. for 2 hours.After cooling down, the reaction mixture is filtered and washed withwater to give 11.45 g of product, m.p.: 129°-132° C. Afterrecrystallization of the latter product from 215 ml of acetonitrile, 9.1g of title compound are obtained.

Analysis for C₂₀ H₂₃ Cl₂ NO₂ (molecular weight 380.30) calculated: C63.16; H 6.10; Cl 18,65; N 3.68%; found: C 62.94; H 6.17; Cl 18.41; N3.48%.

EXAMPLE 2 Preparation of3-[4-(4-Chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dichlorophenyl)propanol

After adding 12.93 g (0.03 mol) of3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dichlorophenyl)propanonehydrochloride to a solution of 1.2 g (0.03 mol) of sodium hydroxide in50 ml of methanol, 1.17 g of sodium borohydride are portionwise added tothe above mixture over 1 hour. After terminating the addition, thereaction mixture is boiled under reflux for 3 hours, then the reactionmixture is poured into 150 ml of water. The major part of methanol isdistilled off from the so-obtained oily precipitate, which is then twiceextracted with 50 ml of ethyl acetate each. After evaporating thesolvent, 12.3 g of evaporation residue are obtained to give acrystalline product on addition of 50 ml of diisopropyl ether. In thisway 8.32 g of title product are obtained, which is recrystallized from28 ml of isopropanol to obtain 6.3 g of title compound, m.p.: 96°-98° C.

Analysis for C₂₀ H₂₀ Cl₃ NO (molecular weight 396.74) calculated: C60.54; H 5.08; Cl 26.81 N 3.53%; found: C 60.80; H 5.03; Cl 26.62; N3.60%.

The compounds listed hereinafter are prepared as described above byusing the appropriate propanone derivatives of formula (II) as startingmaterials. The hydrochloride salts are obtained by adding ethanolichydrogen chloride solution to the corresponding base.

1)1-[4-(4-Chlorobenzyl)phenyl]-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanol,yield 93.2%, m.p.: 135°-137° C.;

2) 1-[4-(4-chlorobenzyl)phenyl]-3-(4-phenyl-1-piperidyl)propanol, yield93.8%, m.p.: 98°-101° C.;

3)1-[4-(4-chlorobenzyl)phenyl]-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butanol,yield 78.5%, m.p.: 108°-111° C.;

4) 3-[4-(4-fluorophenyl)-1-piperidyl]-1-(1,1'-biphenyl-4-yl)propanol,yield 90.7%, m.p.: 129°-132° C.;

5)1-phenyl-2-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydro-1-pyridyl]ethanol,yield 80.5%, m.p.: 188°-190° C.;

6)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-2-methyl-1-phenyl-propanol,yield 80.9%, m.p.: 103°-105° C.;

7)1-(4-chlorophenyl)-3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]propanol,yield 82.8%, m.p.: 154°-155° C.;

8)1-(4-chlorophenyl)-3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-2-methylpropanol,yield 84.0%, m.p.: 110°-112° C.;

9)1-(4-chlorophenyl)-2-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]ethanol,yield 60.4%, m.p.: 152°-153° C.;

10)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(3-methoxyphenyl)propanol,yield 87.4%, m.p.: 100°-102° C.;

11) 1-(4-chlorophenyl)-3-[4-(4-chlorophenyl)-1-piperidyl]propanol, yield84.7%, m.p.: 152°-154° C.;

12) 1-(4-chlorophenyl)-3-[4-(4-fluorophenyl)-1-piperidyl]propanol, yield70.5%, m.p.: 108°-110° C.;

13)1-(4-chlorophenyl)-3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propanol),yield 74.1%, m.p.: 141° C.;

14)1-(4-fluorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanol,yield 93.4%, m.p.: 116°-118° C.;

15)1-(2,4-dichlorophenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanol,yield 78.8%, m.p.: 146°-148° C.;

16)1-(2,4-dimethoxyphenyl)-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanol,yield 69.2%, m.p.: 129°-130° C.;

17)4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(4-fluorophenyl)butanol,yield 90.1%, m.p.: 103°-105° C.;

18)1-[4-(4-chlorobenzyl)phenyl]-4-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]butanol,yield 90.7%, m.p.: 104°-105° C.;

19)1-(4-cyanophenyl)-3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]propanol,yield 76.5%, m.p.: 117°-118° C.;

20)1-{4-[2-(4-chlorophenyl)ethyl]phenyl}-3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propanol,yield 83.1%, m.p.: 158°-160° C.;

21)1-(4-cyanophenyl)-3-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]propanol,yield 74.7%, m.p.: 144°-145° C.;

22) 1,2-diphenyl-3-[4-hydroxy-(4-chlorophenyl)-1-piperidyl]propanol,yield 68.7%, m.p.: 150°-151° C.;

23)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-[4-(2-picolyl)phenyl]propanol,yield 40.0%, m.p.: 129°-131° C.;

24)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1,2-diphenylpropanol,yield 82.7%, m.p.: 135°-137° C.;

25)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(4-methoxyphenyl)propanol,yield 82.9%, m.p.: 116°-118° C.;

26) 1-(1-naphthyl)-3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propanol,yield 88.8%, m.p.: 93°-94° C.;

27)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(1-naphthyl)propanol,yield 75.4%, m.p.: 122°-123° C.;

28)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(2,4-dimethoxyphenyl)propanol,yield 54.7%, m.p.: 112°-114° C.;

29)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(4-fluoro-3-nitrophenyl)propanol,yield 30.0%, m.p.: 154°-156° C.;

30)1-[4-(4-chlorobenzyl)phenyl]-3-[4-(4-fluorophenyl)-1-piperidyl]propanol,yield 83.4%, m.p.: 94°-95° C.;

31) 1-(1,1'-biphenyl-4-yl)-3-(4-phenyl-1-piperidyl)propanol, yield87.7%, m.p.: 99°-101° C.;

32)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-(4-fluorophenyl)propanol,yield 90.5%, m.p.: 130°-132° C.;

33)1-[4-(4-chlorobenzyl)phenyl]-2-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]ethanol,yield 87.3%, m.p.: 149°-152° C.;

34) 1-(2,4-dichlorophenyl)-3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propanol, yield57.3%, m.p.: 103°-104° C.;

35)1-(1,1'-biphenyl-4-yl)-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanol,yield: 68.8%, m.p.: 190°-197° C.;

36)1-(1,1'-biphenyl-4-yl)-2-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]ethanol,yield: 76.9%, m.p.: 202°-207° C.;

37)2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-(4'-fluoro-1,1'-biphenyl-4-yl)ethanol,yield: 96.6%, m.p.: 207°-210° C.; and

38)4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-[4-(4-fluoro-benzyl)phenyl]butanol,yield: 76.2%, m.p.: 164°-167° C.

EXAMPLE 3 Preparation of Tablets

a) Tablets weighing 150 mg, containing 5 mg of active ingredient each

    ______________________________________                                                        g                                                             ______________________________________                                        Active ingredient 5                                                           Gelatine          3                                                           Magnesium stearate                                                                              2                                                           Talc              5                                                           Potato starch     40                                                          Lactose           95                                                          ______________________________________                                    

b) Tablets weighing 300 mg, containing 50 mg of active ingredient each

    ______________________________________                                                        g                                                             ______________________________________                                        Active ingredient 50                                                          Polyvidone        6                                                           Magnesium stearate                                                                              3                                                           Talc              9                                                           Potato starch     84                                                          Lactose           148                                                         ______________________________________                                    

After wet granulation, the powder mixture containing the ingredientsgiven above under a) or b), respectively is compressed to tablets. Eachtablet weighs 150 mg or 300 mg, respectively and contains 5 or 50 mg,respectively of active ingredient.

We claim:
 1. A compound selected from the group consisting of:(a)1-[4-(4-chlorobenzyl)phenyl]-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanol;(b) 1-[4-(4-chlorobenzyl)phenyl]-3-(4-phenyl-1-piperidyl)-propanol; (c)1-[4-(4-chlorobenzyl)phenyl]-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butanol;(d) 3-[4-(4-fluorophenyl)-1-piperidyl]-1-(1,1'-biphenyl-4-yl)propanol;and (e)3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-)2,4-dichlorophenyl)propanol;or a pharmaceutically acceptable acid addition salt thereof. 2.1-[4-(4-chlorobenzyl)phenyl]-2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethanolor a pharmaceutically acceptable acid addition salt thereof as definedin claim
 1. 3.1-[4-(4-chlorobenzyl)phenyl]-3-(4-phenyl-1-piperidyl)-propanol or apharmaceutically acceptable acid addition salt thereof as defined inclaim 1.4.1-[4-(4-chlorobenzyl)phenyl]-4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butanolor a pharmaceutically acceptable acid addition salt thereof as definedin claim
 1. 5.3-[4-(4-fluorophenyl)-1-piperidyl]-1-(1,1'-biphenyl-4-yl)propanol, or apharmaceutically acceptable acid addition salt thereof as defined inclaim 1.6.3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-)2,4-dichlorophenyl)propanolor a pharmaceutically acceptable acid addition salt thereof as definedin claim
 1. 7. A pharmaceutical composition for treating disordersarising from hypoxia and/or ischaemia, which comprises as activeingredient a therapeutically effective amount of the compound of theformula (I) as defined in claim 1, or a pharmaceutically acceptable acidaddition salt thereof in admixture with one or more pharmaceuticallyacceptable inert carriers.
 8. A method for enhancing the tolerance ofmammals against hypoxic and/or ischaemic states as well as for treatingthe degenerative and functional disturbances arising from hypoxic and/orischaemic results, which comprises the step of administering to amammalian subject to be treated a therapeutically effective amount of acompound of the formula (I) as defined in claim 1, or a pharmaceuticallyacceptable acid addition salt thereof alone or in the form of apharmaceutical composition.